Evidence indicates that environmental factors play a major role in precipitating systemic autoimmunity in genetically susceptible individuals, however, little is known about the mechanisms involved. Certain heavy metals, such as mercury, are potent environmental immunostimulants that produce a number of immunopathologic sequelae, including lymphadenopathy, hypergammaglobulinemia, and even overt systemic autoimmunity. Studies in mice indicate that susceptibility to such metal induced immunopathology is influenced by both MHC and non MHC genes. The aims of this proposal are to define the genetic factors required for mercury induced autoimmunity in a well characterized animal model. Genetic studies will identify loci conferring susceptibility or resistance to mercury induced autoimmunity using F2 intercrosses of SJL/J (susceptible) and DBA/2 (resistant) strains by linkage analysis of mercury induced immunopathologic features to a panel of microsatellite markers spanning the mouse genome. Congenic mice will be generated to define the role of these loci and the corresponding genes will be identified by several approaches. Identification of susceptibility/resistance genes and mechanisms relevant to the immunopathogenesis of mercury induced autoimmunity should provide important insights on the pathogenesis of autoimmunity, and may identify potential targets for intervention.